A5076043614- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Monoclonal and Polyclonal Antibodies Research
- Synthesis and Biological Evaluation
- Immunodeficiency and Autoimmune Disorders
- Reproductive System and Pregnancy
- Platelet Disorders and Treatments
- Hematopoietic Stem Cell Transplantation
- Immune cells in cancer
- Immune Response and Inflammation
- IL-33, ST2, and ILC Pathways
- Chronic Lymphocytic Leukemia Research
- Heparin-Induced Thrombocytopenia and Thrombosis
- Inflammatory Bowel Disease
- Autoimmune and Inflammatory Disorders Research
- HER2/EGFR in Cancer Research
- Climate Change and Health Impacts
- Colorectal Cancer Treatments and Studies
- Cutaneous lymphoproliferative disorders research
- Protein Kinase Regulation and GTPase Signaling
- Macrophage Migration Inhibitory Factor
- Thermoregulation and physiological responses
Daiichi Sankyo (United States)
2025
Medical College of Wisconsin
2008-2024
AbbVie (United States)
2018-2023
Children's Hospital of Wisconsin
2009-2016
Center for Rheumatology
2009
Abstract The population dynamics that enable a small number of regulatory T (TR) cells to control the immune responses foreign Ags by much larger conventional cell subset were investigated. During primary response, expansion and contraction TR occurred in synchrony. Importantly, relative accumulation at peak response significantly exceeded cells, reflecting extensive division within pool. Transfer polyclonal before immunization antagonized both TCR transgenic responses, whereas blocking...
In addition to thymus-derived or natural T regulatory (nT(reg)) cells, a second subset of induced (iT(reg)) cells arises de novo from conventional CD4(+) in the periphery. The function iT(reg) tolerance was examined CD45RB(high)CD4(+) cell transfer model colitis. situ-generated were similar nT(reg) their capacity suppress proliferation vitro and absence vivo accelerated bowel disease. Treatment with resolved colitis, but only when also present. Although required Foxp3 for suppressive...
Regulatory T cells (Tregs), in particular CD4(+) Foxp3(+) cells, have been shown to play an important role the maintenance of tolerance after allogeneic stem cell transplantation. In current study, we identified a population CD8(+) that are induced early during graft-versus-host disease (GVHD), constitute significant percentage entire Treg population, and present all major GVHD target organs. These expressed many same surface molecules as found on Tregs potently suppressed vitro alloreactive...
Abstract The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, has also been implicated tumorigenesis tumor survival. However, it is unknown whether for antitumor responses. We evaluated venetoclax, a selective small-molecule inhibitor of BCL2, would influence the activity checkpoint inhibitors (ICI). demonstrate mouse syngeneic models that venetoclax can augment efficacy ICIs accompanied by increase PD-1+ T effector memory cells....
Phospholipase Cγ1 (PLCγ1) is an important signaling effector of T cell receptor (TCR). To investigate the role PLCγ1 in biology, we generated and examined mice with cell–specific deletion PLCγ1. We demonstrate that deficiency affects positive negative selection, significantly reduces single-positive thymocytes peripheral cells, impairs TCR-induced proliferation cytokine production, activation ERK, JNK, AP-1, NFAT, NF-κB. Importantly, development function FoxP3+ regulatory causing...
Abstract “Natural” regulatory T cells (nTregs) that express the transcription factor Foxp3 and produce IL-10 are required for systemic immunological tolerance. “Induced” (iTregs) nonredundant essential tolerance at mucosal surfaces, yet their mechanisms of suppression stability unknown. We investigated role iTreg-produced iTreg fate in a treatment model inflammatory bowel disease. Colitis was induced Rag1−/− mice by adoptive transfer naive CD4+ carrying nonfunctional allele. At onset weight...
Induced regulatory T (iTreg) and Th17 cells promote mucosal homeostasis. We used a cell transfer model of colitis to compare the capacity iTreg develop in situ following naive CD4(+)CD45RB(hi)T intoRag1(-/-)C57BL/6 or BALB/c mice, prototypical Th1/M1- Th2/M2-prone strains. found that frequency number Foxp3(+)iTreg were significantly reduced C57BL/6 mice compared with strain. also resistant natural Treg immunotherapy. Pretreatment C57BL/6Rag1(-/-)mice IL-4 plus IL-13, M2a but not M1...
The transcription factor Foxp3 is essential for the development of functional, natural Treg (nTreg), which plays a prominent role in self-tolerance. Suppressive Foxp3(+) cells can be generated from naïve T ex vivo, following TCR and TGF-beta1 stimulations. However, molecular contributions different arms these pathways leading to expression are not fully understood. TGF-beta1-activated Smad3 major Foxp3, since TGF-beta1-induced-Treg generation Smad3(-/-) mice markedly reduced abolished by...
Abstract Background: T-DXd showed clinically meaningful antitumor activity in patients (pts) with HER2+ mCRC the phase 2 DC-02 trial (NCT04744831). Exploratory baseline circulating tumor DNA (ctDNA) analyses of HER2 (ERBB2), PIK3CA, and RAS mutation (mut) status blood-based mutational burden were reported previously (Raghav et al. 2024). This study reports relationship between other CRC-related genes efficacy mCRC. Methods For this analysis, data combined from 122 pts enrolled 5.4 6.4 mg/kg...
Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) attributable T cell–mediated inflammation. In this work, we identified unique CD4+ cell population that constitutively expresses β2 integrin CD11c displays biased central memory phenotype transcriptional profile, innate-like properties, increased expression gut-homing molecules α4β7 CCR9. Using several complementary murine GVHD models, determined adoptive transfer early...
Abstract Natural regulatory T (nTreg) cells recognize self-peptides with high affinity, yet the understanding of how affinity influences their selection in thymus is incomplete. We use altered peptide ligands transgenic mice and organ culture to create thymic environments spanning a broad range ligand affinity. demonstrate that nTreg TCR repertoire shaped by affinity-based selection, similar conventional cells. The effect each on two populations distinct, consistent early cell lineage...
The relationship between the TCR repertoires of natural regulatory T cells (nTregs) and conventional CD4(+) (Tconv) capable responding to same antigenic epitope is unknown. In this study, we used TCRβ-chain transgenic mice generate polyclonal nTreg Tconv populations specific for a foreign Ag. from immunized 3.L2β(+/-) TCRα(+/-) Foxp3(EGFP) were restimulated in culture yield nTregs (EGFP(+)) (EGFP(-)) defined by their reactivity. Relative Tconv, expansion was delayed, although higher...
Recurrent exposures to a pathogenic antigen remodel the CD8 + T cell compartment and generate functional memory repertoire that is polyclonal complex. At clonotype level, response conserved influenza antigen, M1 58–66 has been well characterized in healthy individuals, but not patients receiving immunosuppressive therapy or with aberrant immunity, such as those juvenile idiopathic arthritis (JIA). Here we show JIA have reduced number of specific RS/RA clonotypes, indicating decreased clonal...
Heparin-induced thrombocytopenia is a relatively common drug-induced immune disorder that can have life-threatening consequences for affected patients. Immune complexes consisting of heparin, platelet factor 4 (PF4), and PF4/heparin-reactive Abs are central to the pathogenesis heparin-induced thrombocytopenia. Regulatory T (Treg) cells subpopulation CD4 play key role in regulating responses, but their controlling PF4/heparin-specific Ab production unknown. In studies described this article,...
Platelets are a rich source of many cytokines and chemokines including transforming growth factor β 1 (TGF-β1). TGF-β1 is required to convert conventional CD4+ T (Tconv) cells into induced regulatory (iTreg) that express the transcription Foxp3. Whether platelet contents will affect Treg cell properties has not been explored. In this study, we show unfractionated lysates (pltLys) containing efficiently Foxp3 expression in Tconv cells. The common surface phenotype vitro suppressive activity...
CD3 bispecific T-cell engagers (TCE), comprised of a tumor-targeting domain linked to binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected cell-mediated killing tumor cells. Although the majority molecules in clinical development incorporate antibody-based domains, many tumor-associated antigens derive from intracellular proteins are not accessible targeting via antibody. Intracellular processed into short peptide fragments...